Linden3 1 Clinical Fellow, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA 2 Assistant Professor, Department of Critical
Trang 1Evidence-Based Medicine Journal Club
EBM Journal Club Section Editor: Eric B Milbrandt, MD, MPH
Journal club critique
Steroids in early ARDS?
Tarek Aldabbagh1, Eric B Milbrandt2, and Peter K Linden3
1 Clinical Fellow, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
2 Assistant Professor, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
3 Professor, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Published online: 14 th May 2007
This article is online at http://ccforum.com/content/11/3/308
© 2007 BioMed Central Ltd
Critical Care 2007, 11: 308 (DOI 101186/cc5908)
Expanded Abstract
Citation
Annane D, Sebille V, Bellissant E: Effect of low doses of
corticosteroids in septic shock patients with or without early
acute respiratory distress syndrome Crit Care Med 2006,
34:22-30 [1]
Background
Experimental evidence suggests that corticosteroids may be
beneficial in early acute respiratory distress syndrome
(ARDS)
Methods
Objective: To investigate the efficacy of low doses of
corticosteroids in septic shock patients with or without early
ARDS by post hoc analysis of a previously completed
clinical trial
Design: Retrospective analysis of a placebo-controlled,
randomized, double-blind trial of low doses of
corticosteroids in septic shock
Setting: Nineteen intensive care units in France
Subjects: Among the 300 septic shock patients enrolled,
we selected those meeting standard criteria for ARDS at
inclusion
Intervention: Seven-day treatment with 50 mg of
hydrocortisone every 6 hrs and 50 µg of
9-alpha-fludrocortisone once a day
Measurements and main results: There were 177 patients
with ARDS (placebo, n = 92; corticosteroids, n = 85)
including 129 (placebo, n = 67; corticosteroids, n = 62)
nonresponders and 48 (placebo, n = 25; corticosteroids, n =
23) responders In nonresponders, there were 50 deaths
(75%) in the placebo group and 33 deaths (53%) in the
steroid group (hazard ratio 0.57, 95% confidence interval
0.36-0.89, p = 013; relative risk 0.71, 95% confidence interval 0.54-0.94, p = 011) The number of days alive and off the ventilator was 2.6 +/- 6.6 in the placebo group and 5.7 +/- 8.6 in the steroid group (p = 006) There was no significant difference between groups in responders There was no significant difference between groups in the two subsets of patients without ARDS Adverse events rates were similar in the two groups
Conclusion
This post hoc analysis shows that a 7-day treatment with
low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS
Commentary
It is difficult to imagine a topic that generates a more heated debate than that of the role of corticosteroids (steroids) in ARDS First described in 1967 [2,3], ARDS is an acute life threatening condition characterized by excessive and protracted systemic inflammation Given their anti-inflammatory properties, steroids have been evaluated as a potential treatment for ARDS using a variety of doses and durations and at various time points in the course of ARDS Short courses of high dose steroids in ARDS are not beneficial [4,5] Interest in this therapy was renewed when
an apparent survival benefit was demonstrated in a single-center randomized trial of low dose prolonged steroids in late ARDS [6]
In the current study, Annane and colleagues explored the effect of seven days of treatment with low dose steroids in septic shock patients with or without early ARDS [1] This
study was a post hoc subgroup analysis of data obtained
previously in another completed clinical trial [7] Among the
300 subjects enrolled in the original trial, there were 177
Trang 2patients with early ARDS, including 129 non-responders to
the short cosyntropin stimulation test (steroids, n = 62;
placebo, n = 67) and 48 responders (steroids, n = 23;
placebo, n = 25) The steroid-treated and placebo groups
were well balanced at baseline Among non-responders with
early ARDS, 28-day mortality was significantly lower in
those receiving steroids (53% vs 75%, p=0.01) There was
no significant difference between groups in the rates of
adverse events, such as superinfection, gastrointestinal
bleeding, or psychiatric disorders Interestingly, there were
no differences in clinical outcomes between the steroid and
placebo groups for the subgroup of early ARDS responders
or for those without early ARDS, regardless of responder
status These results persisted after adjustment for baseline
cortisol, cortisol response, McCabe class, Logistic Organ
Dysfunction score, arterial lactates, and PaO2/FiO2 ratios
The authors conclude that their findings should be
confirmed in multicenter trial
This was a well-done study and an insightful application of
existing clinical trial data to inform the “steroids for ARDS”
debate An obvious limitation is one inherent in any post hoc
subgroup analysis: multiple comparisons can lead to
misleading conclusions To emphasize the danger of post
hoc subgroup analysis, one group demonstrated in data
from a randomized trial that there was a statistically
significant association between astrological birth sign and
the effect of aspirin on mortality in acute myocardial
infarction [8] Such statistical aberrations are more likely
when multiple combinations of subgroups are examined,
especially if the approach is not hypothesis driven This was
not the case in the current study Because this study was
conducted before publication of the ARDS Network low tidal
volume trial [9], the mean ventilator tidal volume in each
group was 9 mL/kg of observed body weight Since lower
tidal volumes reduce inflammation and improve outcome in
ARDS, it is not known whether steroids would still be
beneficial when a low tidal volume strategy is utilized
This and other recent trials raise several interesting issues
In the current study, steroids were of no benefit in septic
shock patients without ARDS, which might lead one to
conclude that the benefit of steroids in septic shock [7] is
due to treatment of ARDS rather than adrenal insufficiency
This might explain the failure of the 500 patient multicenter
CORTICUS trial to show a mortality benefit for steroids in
patients with septic shock, although other explanations have
been offered [10] Supporting the findings of the current
study, Meduri and colleagues recently reported the results
of a five-center 91 patient randomized trial of low-dose
prolonged steroid infusion in early severe ARDS The
authors found significantly improved lung function and ICU
mortality in steroid treated subjects, and a trend toward
lower hospital morality [11] Mean tidal volume was not
reported in this trial, but was likely greater than 6 mL/kg
since the study was conducted between years 1997 and
2002 While the authors did assess adrenal function at
entry, the small size of the trial limited any meaningful
subgroup analysis by cosyntropin responsiveness
Furthermore, the large late crossover rate (control subjects
received steroids if they failed to improve by study days 7 to 9) could have biased results in favor of the steroid group, given the results of another recent trial which suggested harm when steroids were given late in the progression of ARDS [12] This latter trial, in turn, has also been criticized, with some suggesting too rapid weaning of steroids or the permitted use of neuromuscular blockers might explain the failure to find a benefit
Recommendation
As suggested by the authors of the current study [1] as well
as the more recent Meduri and colleagues study [11], a larger randomized controlled trial of low-dose prolonged steroids in patients with early ARDS is warranted Such a trial should stratify patients according to cosyntropin responsiveness and, perhaps, whether they have shock at study entry Furthermore, close attention must be paid to infection surveillance, tight blood glucose control, avoidance
of neuromuscular blockers, and the use of low tidal volume ventilation
Competing interests
The authors declare no competing interests
References
1 Annane D, Sebille V, Bellissant E, Ger-Inf-05 Study
Group.: Effect of low doses of corticosteroids in septic shock patients with or without early acute
respiratory distress syndrome Crit Care Med 2006,
34:22-30
2 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE: Acute
respiratory distress in adults Lancet 1967,
2:319-323
3 Petty TL, Ashbaugh DG: The adult respiratory distress syndrome Clinical features, factors influencing prognosis and principles of
management Chest 1971, 60:233-239
4 Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate
RM, Sibbald WJ, Kariman K, Higgins S, Bradley R, Metz
CA, : High-dose corticosteroids in patients with the
adult respiratory distress syndrome N Engl J Med
1987, 317:1565-1570
5 Luce JM, Montgomery AB, Marks JD, Turner J, Metz
CA, Murray JF: Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with
septic shock Am Rev Respir Dis 1988, 138:62-68
6 Meduri GU, Headley AS, Golden E, Carson SJ,
Umberger RA, Kelso T, Tolley EA: Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized
controlled trial JAMA 1998, 280:159-165
7 Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay
E, Troche G, Chaumet-Riffaut P, Bellissant E: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic
shock JAMA 2002, 288:862-871
8 ISIS-2 (Second International Study of Infarct Survival)
Collaborative Group: Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2 ISIS-2 (Second International Study
Trang 3of Infarct Survival) Collaborative Group Lancet
1988, 2:349-360
9 The ARDS Network: Ventilation with lower tidal
volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory
distress syndrome The Acute Respiratory Distress
Syndrome Network N Engl J Med 2000,
342:1301-1308
10 Shorr AF: Endocrine issues in the ICU Medscape
Critical Care 2007,
http://www.medscape.com/viewarticle/550216
Accessed April 23, 2007
11 Meduri GU, Golden E, Freire AX, Taylor E, Zaman M,
Carson SJ, Gibson M, Umberger R:
Methylprednisolone Infusion in Early Severe
ARDS*Results of a Randomized Controlled Trial
Chest 2007, 131:954-963
12 Steinberg KP, Hudson LD, Goodman RB, Hough CL,
Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M:
Efficacy and safety of corticosteroids for persistent
acute respiratory distress syndrome N Engl J Med
2006, 354:1671-1684